Novel regulation of vascular dementia

Abstract
Vascular dementia (VaD) is the second most common cause of dementia, often triggers progressive
cognitive impairment similar to that of Alzheimer’s disease (AD). The current treatment strategies focusing on
local lesions for AD and dementia have not led to satisfactory outcomes. Therefore, comprehensively
understanding of the pathogenesis of VaD and AD is urgently required to address the unmet scientific and clinical
needs. Vascular pathologies across all vasculature have also been linked to VaD and AD. Most notably,
atherosclerosis, stroke and hypertension accelerate the progression of cognitive impairments and dementia of
all causes. Multiple large genome-wide studies identify the atherosclerosis risk gene apolipoprotein E (APOE)
as a strong genetic risk factor for AD. However, despite shared genetic risk factors, atherosclerosis and AD are
often separated in clinical management and mechanistic studies. Pan-vascular diseases represented by
coronary artery disease, ischemic stroke, aneurysm and peripheral artery disease are all associated with VaD,
thus, investigating pan-vascular changes that impact cognitive functions may open up new avenues to
understand VaD and AD. The current application represents our long-term goals to uncover novel mechanisms
linking vascular dysfunctions in the cardio and cerebrovascular systems to VaD and AD. Our effort has led to
the discovery of a new role of the Runt-related transcription factor 2 (Runx2) in regulating both aortic and cerebral
vascular pathologies and cognitive functions. We and others previously reported that Runx2 is an integral
regulator for vascular calcification. Our preliminary studies identified novel function of Runx2 in regulating
atherosclerosis, arterial stiffness, cerebral blood flow and cognitive function in mice; and uncovered upregulation
of Runx2 in aging, atherosclerosis and AD mice as well as in human AD/VaD tissues. Single cell RNA
sequencing analysis further discovered a novel regulation of Runx2 on SMC phenotypic switch, beyond its known
activity in promoting SMC calcification. With an array of molecular, biochemical, proteomics and bioinformatics
approaches, preliminary studies uncovered Runx2 interaction with an essential contractile SMC regulator, serum
response factor (SRF), supporting a novel Runx2/SRF regulatory network in SMC phenotypic switch and
calcification. Elucidating the novel function of Runx2 and Runx2-dependent signaling in regulating VaD will
provide new insights to fill the knowledge gaps, which may lead to novel strategies for clinical management or
treatment of VaD and AD.

Grant Number: 5R01AG082839-03
NIH Institute/Center: NIH
Principal Investigator: Yabing Chen